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      Microbes in Oncology: Controllable Strategies for Bacteria Therapy

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          Abstract

          Bacterial therapy is an emerging method of tumor treatment. By utilizing wild-type bacteria or engineered bacteria to treat solid tumors, bacterial therapy has recently attracted attention due to its high therapeutic specificity. Although many bacterial strains have been tested in animal models or have even advanced to clinical trials, the efficacy of bacterial therapy remains undesirable. The lack of efficient control methods could cause side effects as well as insufficient therapeutic efficiency, both of which are urgent problems for bacterial therapy. Therefore, some studies have constructed bacteria with inducible plasmid or adsorption with responsive nanoparticles, which improved controllability and specificity during bacterial therapy. Herein, we introduce the unique advantages of bacteria in cancer treatment and highlight the issues associated with the application of bacterial therapy, focusing on the incorporation of various methodologies in the advancement of some controllable strategies in bacterial therapy.

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          Most cited references 60

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          Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer.

          GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity. © 2015 by American Society of Clinical Oncology.
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            Tumor microenvironment and therapeutic response

             Yun Dai,  Ting J Wu (2017)
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              Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma.

              A strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purI and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase I study of the intravenous infusion of VNP20009 to patients with metastatic cancer. In cohorts consisting of three to six patients, 24 patients with metastatic melanoma and one patient with metastatic renal cell carcinoma received 30-minute intravenous bolus infusions containing 10(6) to 10(9) cfu/m(2) of VNP20009. Patients were evaluated for dose-related toxicities, selective replication within tumors, and antitumor effects. The maximum-tolerated dose was 3 x 10(8) cfu/m(2). Dose-limiting toxicity was observed in patients receiving 1 x 10(9) cfu/m(2), which included thrombocytopenia, anemia, persistent bacteremia, hyperbilirubinemia, diarrhea, vomiting, nausea, elevated alkaline phosphatase, and hypophosphatemia. VNP20009 induced a dose-related increase in the circulation of proinflammatory cytokines, such as interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, and IL-12. Focal tumor colonization was observed in two patients receiving 1 x 10(9) cfu/m(2) and in one patient receiving 3 x 10(8) cfu/m(2). None of the patients experienced objective tumor regression, including those patients with colonized tumors. The VNP20009 strain of Salmonella typhimurium can be safely administered to patients, and at the highest tolerated dose, some tumor colonization was observed. No antitumor effects were seen, and additional studies are required to reduce dose-related toxicity and improve tumor localization.
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                Author and article information

                Journal
                BIOI
                BIO Integration
                BIOI
                Compuscript (Ireland )
                2712-0082
                2712-0074
                01 January 2021
                24 November 2020
                : 1
                : 4
                : 185-192
                Affiliations
                1Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, P. R. China
                2CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
                Author notes
                *Correspondence to: Zhiyi Chen and Fei Yan, E-mail: zhiyi_chen@ 123456gzhmu.edu.cn ; fei.yan@ 123456siat.ac.cn
                Article
                bioi20200025
                10.15212/bioi-2020-0025
                Copyright © 2020 The Authors

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See https://bio-integration.org/copyright-and-permissions/

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